European Journal of Endocrinology (2009) 160 10111018

ISSN 0804-4643

CLINICAL STUDY

The prevalence and characteristic features of cyclicity and variability in Cushings disease
Krystallenia I Alexandraki1,2, Gregory A Kaltsas1,2, Andrea M Isidori1, Scott A Akker1, William M Drake1, Shern L Chew1, John P Monson1, G Michael Besser1 and Ashley B Grossman1
1 Department of Endocrinology, St Bartholomews Hospital, London EC1A 7BE, UK and 2Division of Endocrinology, Department of Pathophysiology, School of Medicine, Laiko General Hospital, National & Kapodistrian University of Athens, Athens 115 27, Greece

(Correspondence should be addressed to A B Grossman; Email: [email protected])

Abstract
Objective: Cyclical Cushings syndrome may render the diagnosis and management of Cushings disease difcult. The aim of the present study was to investigate the prevalence of cyclicity and variability in patients with Cushings disease, and to identify putative distinctive features. Design: Retrospective case-note study. Methods: We analysed the case records of 201 patients with Cushings disease in a retrospective casenote study. Cyclicity was considered as the presence of at least one cycle, dened as a clinical and/or biochemical hypercortisolaemic peak followed by clinical and biochemical remission, followed by a new clinical and/or biochemical hypercortisolaemic peak. The uctuations of mean serum cortisol levels, as assessed by a 5-point cortisol day curve, dened the variability. Results: Thirty (14.9%; 26 females) patients had evidence of cyclicity/variability. Cycling patients were older but no difference in sex or paediatric distribution was revealed between cycling and noncycling patients. The median number of cycles was two for each patient, and 4 years was the median intercyclic period. A trend to lower cure rate post-neurosurgery and lower adenoma identication was observed in cycling compared with non-cycling patients. In multivariate analysis, older patients, longer follow-up, female sex and no histological identication of the adenoma were associated with an increased risk of cyclic disease. Conclusions: This large population study reveals that cyclicity/variability is not an infrequent phenomenon in patients with Cushings disease, with a minimum prevalence of 15%. Physicians should be alert since it can lead to frequent problems in diagnosis and management, and no specic features can be used as markers. European Journal of Endocrinology 160 10111018

Introduction
Cushings syndrome (CS) due to excess endogenous cortisol production has been occasionally described as cyclical (1) but with variable other descriptions such as periodic hormonogenesis (2), unpredictable hypersecretion of cortisol (3), uctuating steroid excretion (4, 5) or intermittent CS (6). It has been more frequently described in pituitary-dependent CS, Cushings disease, having being characterized by periodic increases and decreases in cortisol levels, clinically and/or biochemically documented (2, 7, 8). However, it has been considered to be an uncommon phenomenon, since only a few small series and case reports conrm its presence (9, 10). It is important to consider that acute investigation may be associated with episodes of lowered activity and delays in denitive diagnosis. Similarly, apparent cure after surgical treatment may simply reect a nadir in activity and be falsely reassuring. Furthermore, uctuating disease activity may render
q 2009 European Society of Endocrinology

medical control extremely difcult. Intermittent as well as sustained cortisol hypersecretion might be associated with considerable morbidity and mortality, necessitating effective denitive treatment (11, 12). Although most experienced endocrine physicians recognize this phenomenon, it has proven difcult to dene it robustly. Cyclicity has been commonly dened as the occurrence of three peaks and two troughs of hypercortisolaemia (9), but this cannot be readily applied to all patients since the intercyclic period may vary and may be so long as to defy a clear assessment. Cyclicity has also been reported in patients with adrenal tumours (13) and ectopic ACTH syndrome (14), but it is most described in patients with Cushings disease. Owing to the lack of any comprehensive data on the prevalence of the phenomenon, the aim of the present study was to investigate the presence of cyclicity (dened as the presence of clinical and biochemical peaks and troughs) and of variability (biochemical uctuations of cortisol secretion) in a large
DOI: 10.1530/EJE-09-0046 Online version via www.eje-online.org

1012

K I Alexandraki and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

cohort of patients with Cushings disease. In addition, some characteristics of this discrete patient population have been investigated.

Materials and methods

We analysed retrospectively the data in 201 patients with Cushings disease, consecutively admitted from 1946 through to 2007 to the Department of Endocrinology, St Bartholomews Hospital London, with the authorization of our institutional case-note review committee (registration number 08/76). The diagnosis of Cushings disease was based on the presence of typical symptoms and signs based on a xed departmental protocol, along with detailed biochemical evaluation, including circadian rhythm studies, lowand high-dose dexamethasone suppression tests (LDDST, HDDST), the CRH stimulation test, and bilateral inferior petrosal sinus sampling (BIPSS) with CRH (a routine procedure in our Department from 1985). Conrmation of Cushings disease was based on the histopathological diagnosis of a corticotroph tumour and/or clinical and biochemical remission following transsphenoidal surgery (TTS), and/or biochemical conrmation of ACTH-dependent CS with a central gradient on BIPSS (15). For the present study, the following demographic data were extracted from the case records of each patient: gender, age at presentation, symptoms and signs of hypercortisolism, years of follow-up, diagnostic workup, therapeutic modalities, pituitary imaging studies and pathology results. A cycle was dened as a clear-cut clinical and/or biochemical hypercortisolaemic peak followed by a clinical and biochemical remission and at least by a new clear-cut clinical and/or biochemical hypercortisolaemic state. Cyclicity was considered to be the presence of at least one cycle. The clinical peak was documented by the appearance and disappearance of specic cushingoid features, according to the detailed clinical records. This assessment was based on the registration of changes (improvement or exacerbation) observed using a clinical assessment system with the advantage of collecting information methodically from a single institution on the basis of a consistent protocol in which specic symptoms/signs were assigned as either present or absent. This to some extent eliminates individual variations of the interviewing physicians in data accrual (16, 17), but is similar to many lists extant in the literature (15). The biochemical peak, characterized by the biochemical conrmation of hypercortisolaemia as previously described (15), was assessed using the cortisol daycurve (CDC, involving measuring serum cortisol levels at ve xed times through a day) (18). This assessment was consistently performed in our department, and is based on a normal range established in a
www.eje-online.org

normal control group and supported by an isotopic dilution technique (18). Each cycle was then further characterized as clinical, biochemical, or both. When the hypercortisolaemic state was not present as a cycle but as uctuations of mean serum cortisol levels, assessed by a 5-point CDC, it was dened as variability. Besides the presence of cortisol uctuations, it was arbitrarily decided to conrm variability by the presence of doubling (mean level increase O200% over basal values) or halving (mean level decrease !50% from basal) of the serum cortisol during CDC performance, in the absence of therapy or without a change in therapy in order to minimize nonphysiological changes due to possible assay variability error (9, 1921). As an example of this calculation, we found one patient who rst presented to her general practitioner with clinical CS which then remitted; 3.5 years later her clinical features recurred and she had increased urine free cortisol (UFC); 2 months later her UFC was normal and she suppressed on a LDDST. A further 2 months later her UFC was again increased and she was admitted for diagnostic work-up. She was administered mitotane and the dose remained stable with a CDC between 363 and 423; however, some 6 years from her previous hypercortisolaemic peak on a stable dose of mitotane for 4 years she presented with a CDC 700 nmol/l (Fig. 1). A second patient was not cured by surgery and was treated medically while awaiting the delayed effects of radiotherapy; however, during this period she was difcult to control medically because of variation in her CDC, and after 6 years she nally had bilateral adrenalectomy. As shown in Fig. 2, a hypercortisolaemic peak was present in November 1996 and another in

Figure 1 Cortisol day curve (nmol/l) assessment of a patient under long-term stable medical treatment with varying levels of cortisol. CDC: blood samples were taken at 0900, 1200, 1500, 1800 and 2100 h from the patient, the serum cortisol measured, and the mean value calculated. Individual values and the mean level are shown in the graph. Previous data based on normal volunteers and an isotopic dilution technique demonstrated that in normal subjects the mean of these ve values should lie between 150 and 300 nmol/l. See text for references.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

Cyclicity in Cushings disease

1013

usually monthly, when required, using the mean cortisol levels through the day (CDC). Follow-up assessment was performed yearly after 3 years of conrmed remission. In order to perform a uniform and consistent data analysis, other hormonal data were not analysed since only the CDC was formally assessed in the whole population studied. While the possibility of ectopic CS was considered during follow-up in all the cases of Cushings disease with negative histology, no case of ectopic disease was identied (15). No case of adrenal insufciency was recorded during the periods of remission in any of the patients studied. Post-operative cure was dened by biochemical and clinical remission of CS. The paediatric population was considered to include any patient with Cushings disease !18 years old.
Figure 2 Cortisol day curve (nmol/l) levels in a patient after the conrmation of the diagnosis and following medical treatment after surgical failure. The arrows indicate the time of surgery and following radiotherapy before medical treatment, and the hypercortisolaemic peaks that can be compared as the patient was on the same treatment at these four time points.

Statistical analysis
Values are presented as mean valueGS.E.M. Statistical signicance in the results was accepted at a P value !0.05. The normal distribution of continuous variables was assessed by applying the non-parametric KolmogorovSmirnov test. Comparisons between groups were made by an independent-sample t-test. The MannWhitney U test was performed for variables which were not normally distributed. Correlations between categorical variables were estimated by the c2 test or with Fishers exact test when appropriate. Odds ratio and 95% condence interval for binary outcomes in univariate and multiple logistic models were calculated and reported. Cyclic disease presence was the dependent variable. Analysis was performed using SPSS (version 11.01; SPSS Inc., Chicago, IL, USA) for Windows XP (Microsoft Corp).

August 1997 on unchanged therapy. Two subsequent cycles on unchanged medication revealed peaks in September 1997, September 1998 and December 1999. Finally, as an example of cyclicity before the admission for the conrmation of CS, a patient presented with clinically orid CS to her general practitioner who remitted in 2 weeks; 2 years later another episode of clinically orid CS lasted 2 months. The third peak presented 27 months later when the patient was fully investigated and cured by surgery and radiotherapy. Cyclicity/variability was recorded if present: i) prior to the rst presentation of the investigation of CS and consequently before any therapeutic intervention, based on clinical ground or biochemical data provided by the previous medical history, or ii) after the conrmation of the diagnosis and following any form of acute or chronic therapeutic modality. The length of the cycle was determined as the duration from one apparent peak of clinical or biochemical CS activity until the following peak. The case records of all patients were carefully evaluated according to departmental protocols. Cases with simple progression from a mild form to the overt disease, the on-going effects of chronic treatment such as radiotherapy or mitotane withdrawal, self-changing treatment doses or non-compliance with medication, signicant alcohol consumption or signicant dietinduced weight or incomplete data recording were excluding criteria from the denition of cyclicity or variability. During the follow-up period, clinical parameters and cortisol secretion were assessed at least at 3-month intervals for clinical purposes, or more frequently,

Results
The whole group of the 201 patients (154 women, 76.6%) initially presented at a mean age of 37.6G1.15 (range: 795) years and were followed up for a mean period of 14.1G0.7 (range: from presentation-52) years; 8.5% (17/201) of the total group were !18 years old at presentation. Nine patients of the total cohort were studied only at presentation. Evidence of cyclicity or variability was observed in 30 patients, of which 26 were female. These patients had a mean age of 42.3G2.0 years at presentation and were followed up for a mean period 14.8G1.6 (range: from presentation-30) years. The cycling did not differ from the non-cycling group in sex ratio or years of followup, but did differ in age at presentation. Cyclicity/variability was present in 16.88% (26/154) of females and in 8.52% (4/47) of males; 1/17 (5.88%) of the paediatric patients showed cyclicity (Tables 1 and 2). In 27 (90%) of these patients there was recorded at least one cycle (median: 2; range: 14) and variability
www.eje-online.org

1014

K I Alexandraki and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

in 12 (40%). In a total of 54 recorded cycles, eight were only clinical, 39 clinical and biochemical and seven biochemical alone. The mean cycle length was 3.8G0.6 years. Only in one patient was a stable intra-cyclic period every 1.5 years in two cycles observed. Evidence of cyclic disease before diagnosis was present in 12 patients, before diagnosis and during follow-up in nine patients, and during follow-up in nine patients. Consequently, in the whole cycling subgroup, evidence of cyclic disease before diagnosis was present in 21 (70%) patients, and in the follow-up in 18 (60%; Table 1). In the 19 patients with cyclicity/variability submitted to TTS, six were cured (post-operative serum cortisol at 0900 h!50 nmol/l), while four had remission with recurrence. Of the cured patients only two had postoperative serum cortisol levels !50 nmol/l in the immediate post-operative period, while four patients had higher levels which fell gradually over 37 days. In one not-cured patient, radiotherapy was performed immediately after the documentation of the detectable post-operative serum cortisol levels, confounding further interpretation. A trend for lower cure rates and a lower rate of pituitary adenoma identication in histology was found in the patients showing cyclicity. The presence of a macroadenoma (two in cycling and 28 in the noncycling patients) did not differ between the groups. Eight of the cyclic patients required bilateral adrenalectomy compared with 47 non-cycling patients; the median follow-up period in those subgroups was 23 years (range: 930 years) and 20.5 years (range: 052 years) respectively; Nelsons syndrome was diagnosed in two (of eight) cyclic patients and 19 (of 47) non-cyclic.

Table 2 Summary of the distinctive and common characteristics found in patients with cyclic and non-cyclic disease. Parameters studied Mean age (range) (years) Mean follow up (range) (years) Female (%) Paediatric population (%) Macroadenoma presence Bilateral adrenalectomy Nelsons syndrome Block and replacement treatment Neurosurgery Cured Recurrence Not cured Pathology Adenoma identication Imaging Suggestive/ diagnostic ndings Cyclic (nZ30) Non-cyclic (nZ171)

P 0.02 0.68 0.24 0.48 0.53 0.90 0.70

42.3G2.0 (1772) 36.8G1.1 (795) 14.8G1.6 (030) 26/30 (86.67%) 1/30 (3.33%) 2 (6.67%) 8 (26.67%) 2/8 (25%) 2 (6.67%) nZ19 6 (31.58%) 4 (21.05%) 9 (47.37%) nZ19 9/19 (47.37%) nZ30 19 (63.3%) 14.0G0.8 (052) 128/171 (74.85%) 16/171 (9.36%) 67 (16.37%) 47 (27.49%) 19/47 (40.4%) (K) nZ127 67 (52.76%) 12 (9.45%) 48 (37.79%) nZ127 83/127 (65.35%) nZ156 109 (69.87%)

0.09

0.09 0.52

P!0.05 is taken as statistically signicant, results at this level are indicated in bold.

Table 1 Summary of the characteristic features of cyclicity and variability in the population studied. Parameters studied Overall, prevalence of cyclicity or variability Prevalence of cyclicity Prevalence of variability Female population Male population Paediatric population (17 patients, !18 years) (%) Median number of cycles (range) Length of cycles (meanGS.E.M., years) Type of 54 cycles Clinical cycles Clinico-biochemical cycles Biochemical cycles Time of diagnosis Before diagnosis After treatment Before diagnosisCafter treatment Prevalence of cyclicityCvariability Prevalence of cyclicity only Prevalence of variability only Cyclic population 30/201 (14.9%) 27/201 (13.43%) 12/201 (5.97%) 26/30 (86.67%) 4/30 (13.33%) 1/17 (5.88%) 2 (14) 3.8G0.6 (0.226) 8 (14.8%) 39 (72.2%) 7 (13.0%) 12 (40%) 9 (30%) 9 (30%) 9 (30%) 18 (60%) 3 (10%)

Two cyclic patients were controlled with block-andreplacement modalities but no patients in the noncycling group required this treatment. Interestingly, imaging studies suggested or conrmed the presence of an adenoma (including macroadenomas) at the rst presentation in 19 cycling patients and 109 non-cycling (Table 2). In four (13.3%) patients we noted a clear paradoxical rise in serum cortisol level following either the LDDST or HDDST. Variability in the signs and symptoms of hypercortisolism are reported in Table 3. Only gastrointestinal symptoms and galactorrhoea in the females appeared to differ between cyclic and non-cyclic patients, but after allowance for multiple comparisons this was no longer statistically signicant. Older patients were found more likely to have a cyclic disease in univariate analysis. In multivariate analysis, however, after adjusting for other covariates, older patients, longer follow-up and female sex were associated with an increased risk of cyclic disease, whereas adenoma identication was associated with a signicantly lower risk for cyclic disease (Table 4). No difference was found between the patients with only cyclicity, with cyclicity and variability, or only variability, in terms of age, years of follow-up, cure rates after neurosurgery, imaging or pathologic ndings.

www.eje-online.org

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

Cyclicity in Cushings disease

1015

Table 3 Symptoms and signs of hypercortisolism in the two populations. Cyclic (nZ30) Non-cyclic (nZ171) 139 (81.3%) 86 (50.1%) 111 (64.9%) 118 (69.0%) 83 (48.5%) 50 (29.2%) 101 (59.1%) 56 (32.7%) 64 (37.4%) 55 (32.2%) 51 (29.8%) 30 (17.5%) 62 (36.3%) 71 (41.5%) 52 (30.4%) 36 (21.5%) 41 (24%) 31 (18.1%) 37 (21.6%) 32 (18.7%) 49 (28.7%) 35 (20.5%) 29 (17%) 38 (22.2%) 29 (17%) 21 (12.3%) 34 (19.9%) 17 (9.9%) 27 (15.8%) 35 (20.5%) 20 (11.7%) 23 (13.5%) 18 (10.5%) 14 (8.2%) 12 (7%) 4 (2.3%) 10 (5.8%) 5 (2.9%) 7 (4.1%) 10 (5.8%) 3 (1.8%) 13 (7.6%) 9 (5.3%) nZ128 103 (80.5%) 35 (27.3%) 63 (49.2%) 6 (4.7%)

Discussion
In this study, it has been shown that cyclical or variable CS as dened by specic diagnostic criteria had a prevalence of w15% in a large series of patients with Cushings disease, of whom 70% showed cyclicity or variability before the diagnosis was made and any therapy initiated. It is interesting that very similar percentages of 17% (42% with the rst evidence postoperatively) (22) and 18% (50% with the rst evidence post-operatively) (23) were reported in small series of patients submitted to neurosurgical treatment, although a somewhat higher gure was suggested in an early series from Northern Ireland (24). If cyclicity is a feature of the patients presentation, conrmation of the diagnosis can be difcult, particularly if the patient is evaluated during the period of cycling out (24). The diagnostic work-up may be particularly difcult in this trough period, as at that time the routine diagnostic tests may all be apparently normal. Such variability may also interfere with effective treatment before denitive cure; in the rst place, post-operative cure may be mistakenly ascribed to effective surgery when the disease is simply in an inactive phase. Furthermore, the use of medical therapy may be complicated by variability in the control of the disease which may lead to alternating periods of overand under-treatment, increasing the necessity for more denitive therapy such as bilateral adrenalectomy. However, the nding of an approximately similar frequency of cyclicity being present before and after treatment does not indicate any particular period in the natural history to be more important, even if cycles were more commonly identied before treatment. We noted that most often two cycles, three peaks, were seen in each patient with an intercyclic period of w4 years. Interestingly, a stable intra-subject periodicity of cycles was not observed, other than in a single patient. This would imply that regular cyclicity with 12 h to 85 days periodicity, as has been previously suggested, can clearly occur, but seems much less frequent than more irregular and unpredictable uctuations. (2, 10, 25). Isolated clinical and biochemical cycles showed similar frequencies: clinical along with biochemical cycles were the most commonly identied, implying no additive information from laboratory data for the investigation of cyclicity. This nding suggests the importance of the signs and symptoms as being a harbinger of a new hypercortisolaemic peak. On the other hand, laboratory data are clearly important in conrming such variability, and this might be aided by the use of home-testing with salivary cortisol (26); this has previously been shown to be particularly useful in establishing the denitive diagnosis and follow-up of cyclic patients with rapid uctuations in hormonal secretion (3). The population demonstrating cyclicity and variability do not seem to show any special dening characteristics, although the group as a whole had a
www.eje-online.org

Parameters studied

P 0.22 0.07 0.84 0.29 0.55 0.09 0.11 0.54 1.00 0.68 0.53 0.03 0.84 0.23 1.00 0.35 0.50 0.15 0.35 0.33 0.66 0.81 0.44 1.00 0.80 0.56 0.81 0.53 1.00 0.46 0.77 1.00 1.00 0.73 0.71 0.23 1.00 1.00 1.00 1.00 0.49 0.22 0.47 0.57 1.00 0.83 0.02

Cushingoid appearance 22 (73.3%) Easy bruising/ecchimosis 21 (70%) Weight gain 19 (63.3%) Hypertension 18 (60%) Proximal myopathy/proximal 17 (56.7%) muscles wasting Depression 14 (46.7%) Obesity/central adiposity 13 (43.3%) Thin skin 12 (40%) Change in exercise ability 12 (40%) Headaches/migraines 11 (36.7%) Oedema 11 (36.7%) Gastrointestinal symptoms 11 (36.7%) Buffalo hump/cervival or 10 (33.3%) intrascapular fat pad Striae 9 (30%) Skeletomuscular/joints 9 (30%) aches Disuric symptoms 9 (30%) Infection 9 (30%) Skin pigmentation 9 (30%) Cardiovascular 9 (30%) disease/symptoms Fatigue 8 (26.7%) Acne 7 (23.3%) Other psychiatric disorders 7 (23.3%) Dizziness/drops 7 (23.3%) attacks/lethargy Visual disturbances 6 (20%) Abnormal carbohydrate 6 (20%) metabolism Emotional lability 5 (16.7%) Skin disorders 5 (16.7%) Sleep disorders 4 (13.3%) Flushing/red face 4 (13.3%) Sexual dysfunction 4 (13.3%) Osteoporosis/fracture 4 (13.3%) Neurological symptoms 4 (13.3%) Anxiety/panic 3 (10%) Increased sweating 3 (10%) Hair thin/dry 3 (10%) Poor healing 2 (6.7%) Fundus abnormalities 2 (6.7%) Loss of weight 1 (3.33%) Renal calculi 1 (3.3%) Thirst/polydipsia 1 (3.3%) Thyroid disorders 1 (3.3%) Mental alterations 0 (memory/concentration disturbances, slowness) Poor growth/short stature 0 Female population nZ26 Hirsutism 23 (88.5%) Virilization 6 (23.1%) Menstrual irregularity 12 (46.2%) Galactorrhoea 5 (19.2%)

P!0.05 is taken as statistically signicant before adjustment for multiple comparisons, results at this level are indicated in bold.

However, the presence of cyclicity was more prevalent before diagnosis as opposed to being seen in the followup period (PZ0.02); variability was equally present before as well as after treatment.

1016

K I Alexandraki and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

Table 4 The association of the parameters studied in terms of the presence of cyclic disease. Results from univariate analysis Factors studied Age at presentation Years of follow up Sex Adenoma identication on pathologic specimen Cure (versus recurrence/ persistent disease) Radiologic evidence of pituitary abnormality Bilateral adrenalectomy performed Macroadenoma presence OR 1.03 1.01 2.10 0.43 2.06 0.75 0.94 0.53 95% CI 1.001.05 0.971.05 0.696.37 0.171.17 0.656.48 0.331.69 0.392.25 0.112.43 P value 0.05 0.72 0.19 0.09 0.22 0.48 0.88 0.41 Results from multiple analysis OR 1.04 1.08 6.18 0.30 2.12 0.70 0.52 0.62 95% CI 1.001.09 1.001.16 1.1234.27 1.000.96 0.706.41 0.182.79 1.002.75 0.103.72 P value 0.03 0.05 0.04 0.04 0.18 0.61 0.44 0.60

P!0.05 is taken as statistically signicant, results at this level are indicated in bold.

slight but signicantly higher mean age; this may reect the impact of such variability in delaying diagnosis. There was no obvious difference between the adult and paediatric groups, but the number of patients in the latter was small. The cure rates in patients with cyclicity/variability showed a trend to be lower compared with the noncycling population with Cushings disease, but the numbers are again small. Low surgical cure rates have been previously reported in cyclic Cushings disease, and are in contrast with the commonly referred 8090% cure rate of Cushings disease (27, 28). However, the apparent low cure rates in the total population may simply reect the fact that patients were recruited over a prolonged period of time, with low cure rates being seen in the early years that this form of surgery was used. The same trend towards a difference between cyclic and noncyclic disease was observed in terms of the presence of histological conrmation of an adenoma, which was less commonly seen in patients with cyclical disease. These ndings may be prognostically useful in advising such patients, and may even be a determinant of the type of pituitary operation attempted, i.e. total hypophysectomy as opposed to microadenomectomy. Furthermore, the percentage of patients requiring bilateral adrenalectomy did not differ from the general population, although block-and-replacement to control adrenal function appeared to be used in patients with cyclic disease. It has been previously suggested that pituitary-directed medical treatment, such as bromocriptine (29) or sodium valproate (30), might be particularly valuable in these patients, but the evidence for this is slim and in general these agents are not notably effective (31). Imaging studies do not seem to be useful in identifying cyclic disease since the proportion of patients with abnormal imaging was also broadly concordant between the groups. While in general the signs and symptoms also did not seem to differ between the two populations, there appeared to be a difference in gastrointestinal symptoms and in galactorrhoea in females, but it is unclear if those are truly of clinical signicance. We did note the previously described (25) paradoxical responses to dynamic tests observed in a small percentage of this population, further
www.eje-online.org

emphasizing the limitations of dynamic testing in these patients (6, 7, 9, 32, 33): this response has mainly been reported in patients with ACTHindependent primary pigmented nodular adrenal dysplasia (34). However, while clearly clinicians need to be aware of this pitfall in diagnosis, most centres emphasize the utility of the BIPSS in patients with ACTH-dependent CS, along with the vital necessity of assessing the serum cortisol on the day of testing to conrm that the disease is active at the time of the procedure (18). As noted above, salivary cortisol assessment may prove a useful option, offering a more rapid home-assessment of uctuations in cortisol secretion (3, 35). Notably, female sex, longer follow-up period and the older age of patients at presentation seem to increase the risk of identifying cyclic disease. However, it is difcult to conclude that these features can be considered specic, although the need for life-long follow-up is clear. In addition, histological conrmation of an adenoma was found to be less associated with cyclicity. Interestingly, no difference was observed between cyclicity and variability in any of the parameters studied, other than the time of diagnosis, implying that there is no reason to analyse these parameters of cortisol uctuations differently. Such unpredictable hypersecretion, which may or not be periodic, may represent a common patho-physiologic process. The molecular basis for this signicant variability in hormonal release has been little studied in molecular terms (36). Several hypotheses have been suggested to explain the phenomenon, including episodic haemorrhage, the synchronous growth and death of tumour cells (9, 10) or uctuations in adrenalpituitary axis feedback (14). It seems unlikely that there is abnormal hypothalamic control as such regulation should be absent in the presence of an autonomous tumour (9, 28, 3740). One might speculate that the innate circadian rhythmicity of the tumorous corticotrophs is disturbed, which may account for the changes in ACTH output, although the long time course is difcult to reconcile with this theory.

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

Cyclicity in Cushings disease

1017

There are clearly a number of limitations to this study. Firstly, it is retrospective and relied totally on patient recall of the clinical situation before diagnosis, and the reports by the physicians in the medical case records. Hence, the data presented are descriptive. However, we believe that they are clinically useful as they seek to quantify, as far as possible in a retrospective survey (since no prospective studies have been published), such oscillations in clinical and biochemical activity. In addition, the cyclicity or variability of the patients might have been under-diagnosed since we adopted very strict specic criteria. Nevertheless, all patients were followed up in a single unit with unied protocols, such that there was a relatively uniform assessment. Consequently, it can be emphasized that the calculated prevalence reects the minimum prevalence in this idiosyncratic group of patients. In addition, most patients with a diagnosis of Cushings disease are immediately treated and surgically cured, such that residual cyclicity and variability will no longer be seen. However, in spite of these limitations this is the rst large-scale survey of this phenomenon, and its relatively high frequency suggests that there is a necessity for large prospective studies where more biochemical and clinical data can be properly evaluated. While the CDC is not in common use, we have found that it provides a good approximation to biochemical activity (18). The alternative would have been to have used 24 h urinary cortisol excretion, but these assays are less reliably established and subject to errors in collection (19). For a large retrospective survey such day curves might presently represent the best estimate of biochemical activity we have available considering the unknown validity of the other diagnostic tests in cyclic disease (32, 33). In summary, we report a prevalence of w15% of cyclicity and variability in patients with Cushings disease on clinical and/or biochemical criteria, with no particular specic characteristic dening this population which could help to differentiate them from patients lacking cyclicity. Such phenomena may lead to problems in conrmation of the diagnosis and/or result in dilemmas in deciding on initial treatment, particularly when surgery fails requiring bilateral adrenalectomy or medical treatment. We suggest that this is a minimum prevalence, and marked uctuations in cortisol secretion might be a more common characteristic of Cushings disease than previously considered. The absence of commonly accepted criteria for the denition of cyclicity implies the necessity for prospective studies and for the setting of common guidelines. Physicians should be alert to the presence of cyclical CS since its presence inuences the conrmation of diagnosis as well as therapeutic decisions in to order to optimize the effective management of the disease, and to effectively control the potential longterm sequelae.

Declaration of interest
There is no conict of interest that could be perceived as prejudicing the impartiality of the research reported.

Funding
This research did not receive any specic grant from any funding agency in the public, commercial or not-for-prot sector.

References
1 Oates TW, McCourt JP, Friedman WA, Agee OF, Rhoton AL & Thomas WC Jr. Cushings disease with cyclic hormonogenesis and diabetes insipidus. Neurosurgery 1979 5 598603. 2 Bailey RE. Periodic hormonogenesis-a new phenomenon. Periodicity in function of a hormone-producing tumor in man. Journal of Clinical Endocrinology and Metabolism 1971 32 317327. 3 Hermus AR, Pieters GF, Borm GF, Verhofstad AA, Smals AG, Benraad TJ & Kloppenborg PW. Unpredictable hypersecretion of cortisol in Cushings disease: detection by daily salivary cortisol measurements. Acta Endocrinologica 1993 128 428432. 4 Zondek H, Zondek GW & Leszynsky HE. Fluctuability of steroid excretion. Acta Endocrinologica 1957 26 9195. 5 Bassoe HH, Emberland R & Stoa KF. Fluctuating steroid excretion in Cushings syndrome. Acta Endocrinologica 1958 28 163168. 6 Brooks RV, Jeffcoate SL, London DR, Prunty FT & Smith PM. Intermittent Cushings syndrome with anomalous response to dexamethasone. Journal of Endocrinology 1966 36 5361. 7 Atkinson AB, McCance DR, Kennedy L & Sheridan B. Cyclical Cushings syndrome rst diagnosed after pituitary surgery: a trap for the unwary. Clinical Endocrinology 1992 36 297299. 8 Vagnucci AH & Evans E. Cushings disease with intermittent hypercortisolism. American Journal of Medicine 1986 80 8388. 9 Meinardi JR, Wolffenbuttel BH & Dullaart RP. Cyclic Cushings syndrome: a clinical challenge. European Journal of Endocrinology 2007 157 245254. 10 Mantero F, Scaroni CM & Albiger NM. Cyclic Cushings syndrome: an overview. Pituitary 2004 7 203207. 11 Etxabe J & Vazquez JA. Morbidity and mortality in Cushings disease: an epidemiological approach. Clinical Endocrinology 1994 23 479484. 12 Mancini T, Kola B, Mantero F, Boscaro M & Arnaldi G. High cardiovascular risk in patients with Cushings syndrome according to 1999 WHO/ISH guidelines. Clinical Endocrinology 2004 61 768777. 13 Blau N, Miller WE, Miller ER Jr & Cervi-Skinner SJ. Spontaneous remission of Cushings syndrome in a patient with an adrenal adenoma. Journal of Clinical Endocrinology and Metabolism 1975 40 659663. 14 Estopinan V, Varela C, Riobo P, Dominguez JR & Sancho J. Ectopic Cushings syndrome with periodic hormonogenesis a case suggesting a pathogenetic mechanism. Postgraduate Medical Journal 1987 63 887889. 15 Newell-Price J, Bertagna X, Grossman AB & Nieman LK. Cushings syndrome. Lancet 2006 367 16051617. 16 Trainer PJ & Besser GM. St Bartholomews Hospital: The Barts Endocrine Protocols. Edinburgh: Churchill-Livingstone, 1995. 17 Isidori AM, Kaltsas GA, Pozza C, Frajese V, Newell-Price J, Reznek RH, Jenkins PJ, Monson JP, Grossman AB & Besser GM. The ectopic adrenocorticotropin syndrome: clinical features, diagnosis, management, and long-term follow-up. Journal of Clinical Endocrinology and Metabolism 2006 91 371377. 18 Trainer PJ, Eastment C, Grossman AB, Wheeler MJ, Perry L & Besser GM. The relationship between cortisol production rate and serial serum cortisol estimation in patients on medical therapy for Cushings syndrome. Clinical Endocrinology 1993 39 441443.

www.eje-online.org

1018

K I Alexandraki and others

EUROPEAN JOURNAL OF ENDOCRINOLOGY (2009) 160

19 Hellman L, Weitzman ED, Roffwarg H, Fukushima DK & Yoshida K. Cortisol is secreted episodically in Cushings syndrome. Journal of Clinical Endocrinology and Metabolism 1970 30 686689. 20 Krieger DT. Circadian pituitary adrenal rhythms. Advances in Experimental Medicine and Biology 1975 54 169189. 21 Curtis GC. Long-term changes in corticosteroid excretion. In Biorhythms and Human Reproduction, pp 417423. Eds M Ferin, F Halberg, RM Richart & RL Vande Wiele, New York: John Wiley, 1974. 22 McCance DR, Gordon DS, Fannin TF, Hadden DR, Kennedy L, Sheridan B & Atkinson AB. Assessment of endocrine function after transsphenoidal surgery for Cushings disease. Clinical Endocrinology 1993 38 7986. 23 Streeten DH, Anderson GH Jr, Dalakos T & Joachimpillai AD. Intermittent hypercortisolism: a disorder strikingly prevalent after hypophysial surgical procedures. Endocrine Practice 1997 3 123129. 24 Atkinson AB, Kennedy AL, Carson DJ, Hadden DR, Weaver JA & Sheridan B. Five cases of cyclical Cushings syndrome. BMJ 1985 291 14531457. 25 Shapiro MS & Shenkman L. Variable hormonogenesis in Cushings syndrome. Quarterly Journal of Medicine 1991 79 351363. 26 Arnaldi G, Angeli A, Atkinson AB, Bertagna X, Cavagnini F, Chrousos GP, Fava GA, Findling JW, Gaillard RC, Grossman AB, Kola B, Lacroix A, Mancini T, Mantero F, Newell-Price J, Nieman LK, Sonino N, Vance ML, Giustina A & Boscaro M. Diagnosis and complications of Cushings syndrome: a consensus statement. Journal of Clinical Endocrinology and Metabolism 2003 88 55935602. 27 Hofmann BM, Hlavac M, Martinez R, Buchfelder M, Muller OA & Fahlbusch R. Long-term results after microsurgery for Cushing disease: experience with 426 primary operations over 35 years. Journal of Neurosurgery 2008 108 918. 28 Yasuda K & Miura K. Unique type of Cushings disease in clinical prole: cyclic Cushings syndrome and Cushings disease with favorable outcome to a high daily dose of bromocriptine. Nippon Naibunpi Gakkai Zasshi 1994 70 1116. 29 Adachi M, Takayanagi R, Yanase T, Sakai Y, Ikuyama S, Nakagaki H, Osamura Y, Sanno N & Nawata H. Cyclic Cushings disease in long-term remission with a daily low dose of bromocriptine. Internal Medicine 1996 35 207211.

30 Beckers A, Stevenaert A, Pirens G, Flandroy P, Sulon J & Hennen G. Cyclical Cushings disease and its successful control under sodium valproate. Journal of Endocrinological Investigation 1990 13 923929. 31 Alexandraki KI & Grossman AB. Pituitary-targeted medical therapy of Cushings disease. Expert Opinion on Investigational Drugs 2008 17 669677. 32 James VH, Landon J & Wynn V. Oral and intravenous suppression tests in the diagnosis of Cushings syndrome. Journal of Endocrinology 1965 33 515524. 33 French FS, Mace JA, Baggett B, Williams TF & Van Wyk JJ. Cushings syndrome with a paradoxical response to dexamethasone. American Journal of Medicine 1969 47 619624. 34 Stratakis CA, Sarlis N, Kirschner LS, Carney JA, Doppman JL, Nieman LK, Chrousos GP & Papanicolaou DA. Paradoxical response to dexamethasone in the diagnosis of primary pigmented nodular adrenocortical disease. Annals of Internal Medicine 1999 131 585591. 35 Yaneva M, Mosnier-Pudar H, Dugue MA, Grabar S, Fulla Y & Bertagna X. Midnight salivary cortisol for the initial diagnosis of Cushings syndrome of various causes. Journal of Clinical Endocrinology and Metabolism 2004 89 33453351. 36 Dahia PL & Grossman AB. The molecular pathogenesis of corticotroph tumors. Endocrine Reviews 1999 20 136155. 37 Jordan RM, Ramos-Gabatin A, Kendall JW, Gaudette D & Walls RC. Dynamics of adrenocorticotropin (ACTH) secretion in cyclic Cushings syndrome: evidence for more than one abnormal ACTH biorhythm. Journal of Clinical Endocrinology and Metabolism 1982 55 531537. 38 Watanobe H, Aoki R, Takebe K, Nakazono M & Kudo M. In vivo and in vitro studies in a patient with cyclical Cushings disease showing some responsiveness to bromocriptine. Hormone Research 1991 36 227234. 39 Scapagnini U, Van Loon R, Moberg GP, Preziosi P & Ganong WF. Evidence for central norepinephrine-mediated inhibition of ACTH secretion in the rat. Neuroendocrinology 1972 10 155160. 40 Hsu TH, Gann DS, Tsan KW & Russell RP. Cyproheptadine in the control of Cushings disease. Johns Hopkins Medical Journal 1981 149 7783.

Received 4 March 2009 Accepted 8 March 2009

www.eje-online.org